Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease, the etiology of which is unknown. Recently, three different lupus-prone mouse strains have been identified as having a genetic defect in a receptor ligand pair (Fas) which mediates apoptosis. These animal models emphasize the critical importance of lymphocyte apoptosis in maintaining self-nonself discrimination. The Fas apoptotic pathway has thus far been shown to have a significant role in maintaining peripheral tolerance of mature T and B cells. In contrast to data on lymphocytes, little is known about macrophage apoptosis. We have recently shown that activated macrophages presenting antigens are killed by antigen specific Th1 cells through the FasR. Our data suggest a novel mechanism by which FasR-FasL interactions may regulate immune responses at the level of the antigen presenting cell. We hypothesize that Th1 cell-mediated elimination of macrophages is required to maintain self tolerance and that failure to delete macrophages presenting self-peptide contributes to the expression of autoimmunity in Fas-deficient mice. The overall goal of our proposal is to study the functional significance of antigen-presenting cell (APC) apoptosis in normal immunoregulation and in SLE as well as to define which parameters (cytokines, activation and adhesion molecules) are required for Fas-mediated apoptosis of APCs. AIM 1 of this proposal will explore the roles of cytokines as well as macrophage cell surface activation and adhesion molecules in Fas mediated apoptosis. To study the selective effect of macrophage FasR deficiency in vivo (AIM 2), RAG-/MRL/lpr and RAG-/MRL/++ mice will be injected with MRL/++ lymphocytes depleted of macrophages and the onset and severity of autoimmunity compared. In AIM 3, we will examine the function of Fas on another potent APC, the dendritic cell. Our studies will explore further mechanism and functional significance of a novel immunoregulatory pathway between T cells and APCs and will expand our knowledge on the role of macrophages and dendritic cells in immunity and autoimmunity.